Movement Disorders Pharma

List the function of these DOPAMINERGIC PATHWAYS

DOPAMINERGIC PATHWAYS

• Mesocortical pathway

  • Perception, cognition, social behavior

• Mesolimbic pathway

  • Motivation & reward

• Nigrostriatal pathway

  • Motor control (affected in Parkinson’s disease)

    • ↓ activity → extrapyramidal symptoms

• Tuberoinfundibular pathway

  • ↓ activity → ↑ prolactin release

NOTE:

• Antipsychotics work on all except for Mesocortical

1. Describe PD Patho

2. Describe what happens in the normal physiological condition vs PD condition

PD Patho

• Loss of inhibitory dopaminergic neurons in substantia nigra

  • Dopa neurons fire tonically, and not in response to specific sensory inputs

  • Less dopamine release in the neostriatum

• Loss of inhibitory effect of dopamine in neostriatum

  • Less inhibition of

    • stimulatory Motor neurons 

    • inhibitory GABA neurons -> substantia nigra

  • ↓ inhibitory effects of dopamine → ↑ acetylcholine production → abnormal signaling → impaired mobility

---

• Physiological condition

  • Dopamine -> promotes movement by 

    • stimulating direct D1 pathways 

    • inhibiting indirect D2 pathway

• PD Condition:

  • Dopa Deficiency -> 

    • Overact. Indirect D2 pathways 

    • Reduces Direct D1 pathway

  • -> inhibition of the motor thalamus

[REVIEW] basal ganglia pathway

1. Describe LEVODOPA

   • What is it

   • MOA

   • Treats

   • Synergy

2. Describe Carbidopa

   • MOA

   • Synergy Effects

3. List the adverse effects of Both

4. Long term Levodopa complications

5. Drug Interactions

LEVODOPA

• What is it?

  •  dopamine replacement agent

• MOA

  • Dopa can’t cross BBB; Levodopa can -> converts to dopa in C/PNS

• Treats:

  • Parkinson motor symptoms (most effective)

    • bradykinesia & rigidity

• Synergy:

  • Combines w/ carbidopa 

    • Sinemet, Rytary

  • peripheral decarboxylase inhibitors → ↑ bioavailability

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Carbidopa

• MOA

  • Inhibits peripheral DOPA decarboxylase 

    • Levo can’t -> Dopa

  • Does not Cross BBB

• Synergy effects :

  • ↓ levodopa in the periphery → ↑ levodopa to the CNS

  • ↓ dose of levodopa needed by 4- to 5-fold

  • ↓ adverse effects arising from peripheral dopamine

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ADVERSE EFFECTS (Both)

• GI: 

  • N/V

• Cardiovascular: 

  • Orthostatic hypotension;

  • possible arrhythmias

• CNS: 

  • Hallucinations, 

  • confusion, 

  • Psychosis

  • especially in older patients

• Motor

  • Dyskinesias + motor fluctuations w/ chronic therapy

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LONG-TERM LEVODOPA COMPLICATIONS

• Wearing-off

  • Dose effect does not last until next dose.

• On-off phenomenon

  • Sudden unpredictable shifts between mobility and immobility.

• Dyskinesia

  • Involuntary choreiform movements.

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DRUG INTERACTIONS

• Vitamin pyridoxine (B6)

  • Function: ↑ peripheral breakdown of levodopa

  • Can be co-administered with levodopa & carbidopa combination

    • Vitamin B6 increases the rate of aromatic amino acid decarboxylation

    • Carbidopa inhibits this action of Vitamin B6

• Nonselective monoamine oxidase inhibitors (MAOIs)

  • Phenelzine + levodopa → hypertensive crisis 

    • enhanced catecholamine production

Describe DOPAMINE AGONISTS

• Main Uses

• Pt. Profile

• Members/Diseases used for

• Adverse Effects

DOPAMINE AGONISTS

• Main uses

  • Parkinson disease

  • Restless legs syndrome

  • Hyperprolactinemia

• PT. Profile:

  • used in younger patients or as adjuncts

• Members/Diseases used for:

  • Parkinson/RLS

    • Pramipexole & ropinirole

  • Prolactin/pituitary

    • Bromocriptine & cabergoline

  • Transdermal dopamine agonist patch

    • Rotigotine

• Adverse effects: 

  • Hallucinations, 

  • sleep attacks,

  • orthostatic hypotension, 

  • nausea

  • Impulse-control disorders: 

    • Gambling, shopping, hypersexuality

  • Ergot agonists: 

    • Risk of fibrosis

Describe MAO-B INHIBITORS

• Members

• MOA

• Uses

• Adverse Effects

MAO-B INHIBITORS

• Members:

  • Selegiline

  • Rasagiline

  • safinamide

• MOA:

  • ↓ dopamine breakdown → ↑ CNS dopamine

• Uses:

  •  Mild Parkinson disease 

  • adjunct to levodopa

• Adverse effects: 

  • Insomnia; 

  • serotonin syndrome risk

Describe COMT INHIBITORS

• Members

• MOA

• Uses

• Key Distinctino

• AE

COMT INHIBITORS

• Members:

  • Entacapone,

  • tolcapone,

  • opicapone

• MOA: 

  • Inhibit COMT → prolong levodopa effect

    • COMT methylates levodopa → 3-O-methyldopa

    • Carbidopa → ↑ levodopa → ↑ 3-O-methyldopa

    • 3-O-methyldopa competes with levodopa → ↓ levodopa transport -> CNS

• Uses

  • Adjunct to levodopa & carbidopa

• Key distinction: 

  • Tolcapone → hepatotoxicity risk

    • it is also a central COMT Inhibitor

• ADVERSE EFFECTS

  • Dyskinesia, diarrhea, nausea

  • Orange urine: 

    • Benign, especially entacapone

  • Hepatotoxicity

    • Tolcapone

Describe AMANTADINE

• MOA

• USES

• AE

• MOA: 

  • ↑ dopamine release;

  • Decreases Dopa Reuptake

  •  NMDA antagonism

• Use: 

  • Parkinson symptoms; 

  • levodopa-induced dyskinesia

• Adverse effects: 

  • Livedo reticularis,

  • edema, 

  • confusion, 

  • hallucinations

Describe ANTICHOLINERGICS

• Members

• MOA

• Uses

• Avoid/Caution

• AE

ANTICHOLINERGICS

• Members:

  • Benztropine

  • trihexyphenidyl

• MOA:

  • Block muscarinic receptors → ↓ cholinergic activity

• Uses:

  • Tremor 

  • Drug-induced parkinsonism

• Avoid/caution:

  • Older adults, 

  • dementia,

  • BPH, 

  • glaucoma

• ADVERSE EFFECTS

  • Can’t see: Mydriasis, blurred vision

  • Can’t pee: Urinary retention

  • Can’t spit: Dry mouth

  • Can’t sweat: Hyperthermia

  • Can’t think: Confusion, delirium
    
    

NOTE:

• In the Striatum, Dopa urges movement, AcH urges nonmovement; Thus in PD, no Dopa = no movement; also means AcH excess = nonmovement

Describe the PARKINSON TREATMENT STRATEGY

• Older/Severe symptoms

• Younger/mild symptoms

• Wearing-off

• Dyskinesia

• Tremor

• Drug-induced

PARKINSON TREATMENT STRATEGY

• Older/severe symptoms

  • Levodopa/carbidopa

• Younger/mild symptoms

  • Dopamine agonist or MAO-B inhibitor

• Wearing-off

  • Add COMT or MAO-B inhibitor

• Dyskinesia

  • Amantadine

• Tremor

  • Anticholinergic

• Drug-induced

  • Stop culprit ± benztropine/amantadine

Describe ESSENTIAL TREMOR

• What is it?

• Common Sites

• Key Distinction w/ Pd

• Pharmacology

  • First line

  • ALT

  • AE

Essential Tremor

• What is it?

  •  Action/postural tremor

• Common sites: 

  • Hands, head, voice

• Key Distinction w/ PD

  • Essential = action;

  • Parkinson = resting tremor

NOTE:

• Often familial; may improve with alcohol

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PHARMACOLOGY

• First-line: 

  • Propranolol 

  • primidone

• Alt

  • Topiramate, 

  • gabapentin, 

  • benzodiazepines

• AE

  • Propranolol: 

    • Bradycardia, hypotension, bronchospasm

  • Primidone

    • Sedation, dizziness, ataxia

Describe HUNTINGTON DISEASE

• Genetics

• Patho

• Symptoms

• Pharma

  • Family

  • Drugs

  • MOA

  • ALT

  • AE

HUNTINGTON DISEASE

• Genetics:

  • Autosomal dominant CAG repeat 

• Pathology:

  • Caudate atrophy

• Symptoms:

  • Chorea, 

  • Psychiatric symptoms, 

  • cognitive decline

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PHARMACOLOGY

• Family:

  • VMAT2 Inhibitors

• Drugs:

  • Tetrabenazine,

  •  deutetrabenazine

• MOA:

  • VMAT2 inhibition → ↓ dopamine release

    • Reduces Huntington chorea

• Alt:

  • Antipsychotics for chorea/behavioral symptoms

• ADVERSE EFFECTS

  • Depression and suicidality

    • Major Risk

  • Parkinsonism, 

  • akathisia,

  • sedation

Describe DYSTONIA

• What is it?

• Types

• Treatments

Describe Botulinum Toxin

• MOA

• Uses

• AE

DYSTONIA

• What is it?

  • Sustained contractions → abnormal postures

• Types: 

  • Focal, segmental, generalized

• Treatment:

  • Focal dystonia: Botulinum toxin

  • Other Options:

    • Anticholinergics,

    • benzodiazepines, 

    • baclofen

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BOTULINUM TOXIN

• MOA: 

  • Blocks ACh release via SNARE cleavage -> Local chemodenervation → ↓ muscle contraction

• Uses:

  • Dystonia, 

  • spasticity, 

  • migraine,

  • hyperhidrosis

• AE

  • Local weakness;

  • Dysphagia;

  • rare systemic effects

Describe the treatment for TICS & TOURETTE SYNDROME

Treatment:

• Alpha-2 agonists: 

  • Clonidine, guanfacine

  • For Mild tics w/ ADHD

• Antipsychotics

  • Risperidone, aripiprazole, haloperidol

  • More severe tics

• Selected cases: VMAT2 inhibitors

Describe RESTLESS LEGS SYNDROME

• What is it?

• Treatment

RESTLESS LEGS SYNDROME

• What is it?

  • Urge to move the legs

  • Worse at rest and at night

  • Movement provides relief

• Treatment:

  • Treat iron deficiency first

  • Gabapentin/pregabalin = common options

  • Dopamine agonists may cause augmentation

Describe ALZHEIMER DISEASE

• Pathology

• Symptoms

• Treatment/MOA

ALZHEIMER DISEASE

• Pathology: 

  • Amyloid-β plaques + tau tangles

  • Neurotransmitter loss: ↓ Acetylcholine

• Symptoms:

  • Progressive memory +  cognitive decline

• Treatment/MOA:

  • AChE inhibitors: 

    • Donepezil, rivastigmine, galantamine → ↑ ACh

  • Memantine

    • NMDA antagonist → ↓ excitotoxicity

  • Anti-amyloid antibodies

    •  Lecanemab, donanemab → ↓ amyloid pathology

Describe ACETYLCHOLINESTERASE INHIBITORS

• Members

• Uses

• Adverse Effects

• Caution in

ACETYLCHOLINESTERASE INHIBITORS

• Members:

  • Donepezil, 

  • rivastigmine, 

  • galantamine

• Use: 

  • Symptomatic treatment of Alzheimer disease

  • Also Parkinson disease Dementia

    • rivastigmine

• ADVERSE EFFECTS

  • cholinergic excess

    • GI: 

      • N/V diarrhea

    • Cardiac: 

      • Bradycardia, syncope

    • Other

      • Bronchoconstriction, urinary frequency, vivid dreams

• Caution:

  • Asthma/COPD,

  • bradyarrhythmias, 

  • peptic ulcer disease

Describe MEMANTINE

• MOA

• Uses

• Synergy

• AE

MEMANTINE

• MOA:

  • NMDA antagonist → ↓ glutamate excitotoxicity

• Uses:

  • Moderate–severe Alzheimer disease

• Synergy:

  • combined with: Donepezil

• AE:

  • Dizziness, 

  • confusion,

  • headache, 

  • constipation

Describe ANTI-AMYLOID MAb

• Members

• MOA

• Uses

• Req. for prescription?

ANTI-AMYLOID MAb

• Members:

  • Lecanemab, 

  • donanemab

• MOA:

  • Target amyloid-β → plaque clearance

• Use: 

  • Selected patients w/ early symptomatic AD

• Require for Prescription:

  • Confirmed amyloid pathology + MRI monitoring